5. Summary of Data Reported and Evaluation

Printing inks are mixtures of three main types of ingredients:
pigments, vehicles and additives. Pigments used in printing inks
include both inorganic pigments such as carbon black and titanium
dioxide and organic pigments, which are frequently dyes rendered
insoluble by complexing with a metal ion. Most organic pigments
are prepared from azo, anthraquinone and triarylmethane dyes,
and phthalocyanines.

There are five main printing processes, and inks are designed
for the specific process. Lithography and letterpress are collectively
known as the 'paste ink' processes and use inks that are essentially
non-volatile at normal temperatures. Flexography and gravure are
known as the 'liquid ink' processes and are based upon volatile
solvents that evaporate readily at room temperatures. Screen printing
uses inks that fall between the other two groups.

Choice of the vehicle (solvent with resins) for a printing ink
depends on the printing process, how the ink will be dried, and
the substrate on which the image is to be printed. In lithography
and letterpress, where inks are dried by absorption and oxidation,
vehicles are generally mixtures of mineral and vegetable oils
and resins. Flexographic inks, which are designed to dry quickly
by evaporation, can be either water-based or based on organic
solvents (such as ethanol, ethyl acetate, n-propanol or
isopropanol) with a wide variety of resins. Vehicles for gravure
inks, which also dry by evaporation, may also contain aromatic
or aliphatic hydrocarbons and ketones as solvents. Inks for screen
printing use organic solvents that are somewhat less volatile
than those used for flexography or gravure (higher glycol ethers
and aromatic and aliphatic hydrocarbons). Additives in inks include
driers, waxes and plasticizers.

Ultraviolet radiation-cured inks, commonly based on acrylates,
are used in all of the printing processes to varying degrees.

The manufacture of inks consists of dissolving or dispersing resins
in organic solvents or oils to produce the vehicle (varnish),
mixing and dispersing the pigment or dye into the vehicle, introduction
of any additives and packaging. Some or all of these stages may
be done manually or automatically in a batch process or as a continuous
process.

During the manufacture of printing inks, exposure to pigments,
vehicles and additives can occur through inhalation or skin contact
during mixing and dispersion and during clean-up of mixers. Exposures
are higher with liquid inks than with paste inks. During newspaper
printing by letterpress or lithography, the major exposure is
to ink mist. Rotary letterpress was the dominant process for the
production of newspapers until the 1970s. It has now been largely
replaced by web offset litho, in which exposures to ink mist are
considerably lower than for letterpress. In other lithographic
and letterpress printing, the major exposure is to hydrocarbon-based
cleaning solvents and isopropanol from damping solutions. In flexographic,
gravure and screen printing, exposures are mainly to organic solvents.
Historically, some workers in both ink manufacture and printing
were exposed to much higher levels of lead, polycyclic aromatic
hydrocarbons and benzene than today, and the development and use
of modern control technologies have made possible the marked reduction
in solvent and ink mist exposures.

5.2 Human carcinogenicity data

A large volume of epidemiological data deals with potential cancer
risks in printing processes. Because of the presence of a fairly
large number of adequate cohort and case-control studies, it was
considered that there was no marginal benefit in considering further
the descriptive studies based on simple tabulations of death certificate
causes of death and mentions of occupation. In any case, these
latter studies did not provide clear patterns of results.

The evaluation of results of case-control and cohort studies,
in particular those regarding relatively rare neoplasms, was hampered
by the possibility of reporting or publication bias. A second
problem was the poor specificity of exposure information. While
most studies were based on crude designations of the exposure
variable, a few, most notably some of the cohort studies, did
describe risks for subgroups of the printing industry that are
more homogenous in exposure circumstances. The Working Group tried
to identify such subgroup studies with presumably more well-defined
common exposure circumstances. In a small number of studies, there
was an explicit attempt to identify a group of workers exposed
to printing inks. This, like the designation of exposure on the
basis of the job or industry title, is of poor specificity. Further,
most of these were in the context of community-based case-control
studies, and the attribution of exposure was based on job-exposure
matrices, which do not discriminate among subsectors of the printing
industry.

A third problem was that most of the cohort and record-linkage
studies had no information on some important counfounders, notably
cigarette smoking. It has previously been shown that confounding
by smoking is unlikely to distort the relative risk estimate between
occupation titles and lung cancer by more than 30%. For other
sites that are affected by smoking, the maximal bias is likely
to be even lower. The Working Group considered these possible
biases when interpreting results.

Apart from cancers of the lung, oropharynx, urinary bladder and
kidney and leukaemia, which are presented below, the Working Group
considered that the findings are not strong or consistent enough
to be evaluated.

Lung cancer

Ten community-based case-control studies examined the relationship
between lung cancer and occupation and reported results regarding
printing industry and/or printing related occupations. Increased
relative risks were found in eight studies; smoking was controlled
for in six of them and the smoking-adjusted relative risks for
'printing occupations' ranged from 1.1 to 3.3. Two studies reported
findings for exposure to printing inks: both found a positive
association. A Canadian study found that a small excess of lung
cancer detected in printers as a whole was concentrated in printing
process workers and was very high for adenocarcinoma of the lung
in particular.

Six census-based record-linkage studies reported results for lung
cancer. The Swedish study found a statistically significant 60%
excess of lung cancer in blue-collar workers in printing enterprises.
One study in Denmark showed an increased risk only for women employed
in printing, publishing and allied industries. A subsequent Danish
study revealed a slight, statistically significantly increased
risk in printing and bookbinding industry workers; the risk was
higher and still significant in workers employed in newspaper
and magazine production. The Finnish study and the two Italian
studies did not detect a statistically significant increased risk
for lung cancer related to printing occupations.

Among the industry-based studies, five proportionate mortality
studies evaluated the risk for lung cancer. In one study, statistically
significantly increased risks were found among printing trade
workers in two different areas of the United Kingdom. A subsequent,
partially overlapping study in London, United Kingdom, reported
a statistically significant 30% excess of lung cancer among newspaper
printing workers. A third study examined United States newspaper
and commercial pressmen separately; neither newspaper nor commercial
pressmen showed an increased mortality from lung cancer. The other
two proportionate mortality studies in printing workers in the
United States failed to show an increased risk for lung cancer.

Among the industry-based studies, seven standardized mortality
ratio studies examined lung cancer risk in printing trade workers.
Respiratory cancer was elevated in four studies; in none was smoking
controlled. An increased risk for lung cancer was found in the
Italian cohort of newspaper workers. The historical cohort of
trade union members in the United Kingdom printing industry had
a statistically significantly increased risk for lung cancer among
mainly unskilled workers in newspaper letterpress printing (machine
assistants). Newspaper web pressmen in Los Angeles, United States,
showed a nonsignificantly increased lung cancer risk. A Swedish
study of rotogravure printers revealed increased risk from respiratory
cancers.

In addition, in a cohort of United States Army veterans, an increased
smoking-adjusted relative risk for respiratory cancer was found
in 'printing pressmen and plate printers'.

In some studies, it was possible to separate newspaper printing
workers from other less-well defined employment in the printing
industries. Seven cohort studies examined lung cancer risk in
workers employed in the newspaper printing industry, mainly during
the period 1945-1970. Three were proportionate mortality studies,
two of United Kingdom newspaper printing companies and one that
examined United States newspaper pressmen and commercial pressmen
separately. Four were standardized mortality ratio studies of
newspaper web pressmen in Los Angeles, United States, of newspaper
printers in two plants in New York City, United States, of newspaper
workers in one Italian plant and of newspaper machine assistants
who were trade union members in the printing industry in the United
Kingdom. Five of the seven cohort studies reported increased relative
risk estimates ranging from 1.2 to 1.5, of which three were statistically
significant. In none of them was smoking taken into account. In
addition, a Danish record-linkage study found a two-fold, statistically
significantly increased risk for workers in newspaper and magazine
production whose typical job was the operation of rotary letterpress
machines.

Cancer of the oropharynx

The risk for cancer of the buccal cavity and pharynx was examined
in three case-control studies in the United States. One study
on multiple cancer sites showed a smoking-adjusted elevated risk
in printing workers. Another similar study detected a significantly
high smoking- and alcohol-adjusted risk for cancer of the oral
cavity in workers in the printing and publishing industry. A third
case-control study on oropharyngeal cancer did not find an increased
risk among men employed in the printing industries, whereas a
nonstatistically significantly increased risk was found for women.
A nonstatistically significantly increased risk was found in male
workers in printing and bookbinding industries in a Danish record-linkage
study.

Four cohort studies reported results for cancer of the buccal
cavity and pharynx. The United States study that examined separately
newspaper pressmen and commercial pressmen found a higher than
two-fold statistically significantly increased risk in newspaper
pressmen only. Increased risks were not found in a standardized
mortality ratio study of newspaper pressmen in Los Angeles nor
in a cohort of newspaper printers in two plants in New York City.
The cohort of trade union members in the United Kingdom printing
industry found increased risks in non-production workers (editorial
and clerical staff) only.

Urinary bladder cancer

Thirty-five studies have reported findings for urinary bladder
cancer and employment in the printing industry. A positive association
between urinary bladder cancer and either a printing occupation
or employment in the printing industry was reported in 14 of the
23 case-control studies. The range of relative risk estimates
derived from these studies was from 1.1 to 5.6. These associations
were statistically significant in only three of the case-control
studies. Generally, the interpretation of the case-control studies
was limited by their use of broad job and industry categories
such as printers or the printing industry. One study in Spain
reported a nonsignificantly increased relative risk for typesetters
and linotypists.

Six cohort studies and six record-linkage studies have also been
reported. Increased rate ratios were reported in five of the cohort
studies of workers in the printing industry. However, the rate
ratios in two of them were close to 1.0 and a statistically significant
increase was found only for printing pressmen and plate printers
in the cohort of United States Army veterans. Similarly, the relative
risk estimates derived from the record-linkage studies were close
to unity and the only ones that achieved statistical significance
were from the two Danish studies: one study found an increased
risk among men employed in printing and bookbinding industries
and the other among men employed in printing, publishing and allied
industries. Five case-control studies reported results for exposure
to printing inks and urinary bladder cancer risk was observed
to be elevated in all five studies.

Cancer of the kidney

Slight to moderate excesses of cancer of the kidney have been
reported in the printing industry in five industry-based studies
in different cohorts in the United States, and in two record-linkage
studies in Italy and Sweden. Ten cohort studies did not report
results for cancer of the kidney at all. Four case-control studies,
one nested in a cohort of paperboard printing workers and three
representing different populations in three continents reported
odds ratios ranging from 1.3 to 16.6. Most of these were not statistically
significant. By far the most powerful case-control study, a multicentric
study conducted in Australia, Denmark, Germany, Sweden and the
United States, reported a 30% nonsignificant excess associated
with employment in printing and graphic industry.

Leukaemia

Results regarding leukaemia risk in printing workers have been
reported in one case-control study and seven cohort studies. The
case-control study found a nonstatistically significantly increased
risk for printers. Significantly increased risks were found in
two cohort studies.

The proportionate mortality study that examined newspaper pressmen
and commercial pressmen separately found a 60% excess of leukaemia
risk only in newspaper pressmen. In another proportionate mortality
study in printing workers in the United States, a statistically
significantly increased risk for leukaemia was detected primarily
among bindery workers who may have had exposure to benzene. Newspaper
web pressmen in Los Angeles, United States, also showed a higher
than two-fold increased risk. A Swedish study of rotogravure printers
revealed an increased risk for leukaemia, although this was based
on a very small number of cases. Both newspaper web pressmen and
rotogravure printers may have been exposed to benzene and other
organic solvents in the past. Three other cohort studies in newspaper
printing workers in London, United Kingdom, commercial pressmen
in the United States and newspaper printers in New York City failed
to show an increased risk.

Overall, notwithstanding the variability in the results, there
are indications of excess risks among printing process workers
for some types of cancer. In its evaluation of these data, the
Working Group considered the likelihood of publication bias, the
possibility of confounding by cigarette smoking, and the imprecision
and inconsistency of the designation of exposure groups. Based
on these considerations, the Working Group concluded that there
is weak evidence of an increased risk of lung and urinary bladder
cancers among workers in the printing industry.

While there was a suggestion of an increased risk of lung and
urinary bladder cancers in relation to exposure to printing inks,
the quality of the data was weak.

The Working Group noted that the vast majority of epidemiological
studies covered workers who were in the printing industry in North
America or Europe during the middle of the twentieth century.
Very few of the studies included workers whose employment was
after 1980. Given the rapid technological changes that have gone
on in this industry in North America and Europe in the past decade,
it is questionable whether the exposure circumstances that were
prevalent in the past are still prevalent. However, there may
be areas of the world in which the older processes are still prevalent.
Where the technologies have substantially changed from those of
the past and insofar as this has changed the exposure conditions,
the present evaluation may not be relevant.

5.3 Animal carcinogenicity data

Twenty-two different printing inks were tested for carcinogenicity
in one study in mice by subcutaneous injection. The study was
inadequate for evaluation.

5.4 Other relevant data

No consistent association between employment in printing trades
and morbidity from non-malignant diseases has been observed. Solvent-induced
central nervous system damage has been observed in several but
not all studies on employees in printing trades. Ultraviolet radiation-cured
printing inks are a frequent cause of allergic contact dermatitis.

One study suggested that occupational exposures may induce hepatic
damage in printers, but several other studies failed to confirm
this finding.

An early report of an increased risk of anencephalus associated
with paternal employment in printing has not been confirmed in
subsequent studies of neural tube defects. In two studies, an
association between this exposure and cleft lip and/or palate
has been observed. However, in one of these, the association was
apparent only for cleft palate, and in the other only for cleft
lip, and no noteworthy association has been observed in a further
three studies. In a single study in rats, dermal exposure to newspaper
inks had no effect on sperm numbers or motility, vaginal cytology
or oestrus cycle length.

An increased frequency of chromosomal aberrations in peripheral
lymphocytes in printing workers exposed to inter alia toluene
was found in two studies, but not in two other studies. In one
study, an increased frequency of chromosomal aberrations was found
in workers exposed to toluene and benzene. In one study of a group
exposed to toluene, an increased frequency of sister chromatid
exchange was found, but not in two other studies. In one study
of printers exposed to lead, increased frequencies of chromosomal
aberrations and sister chromatid exchange were found. In one study,
an increased frequency of micronuclei was observed in printing
workers exposed to toluene. In one study of volunteers exposed
to toluene, no increase in sister chromatid exchange was observed
in lymphocytes.

5.5 Evaluation

There is limited evidence that occupational exposures in
printing processes arecarcinogenic.

There is inadequate evidence for the carcinogenicity in
humans of printing inks.

There is inadequate evidence for the carcinogenicity in
experimental animals of printing inks.